Pharmaceutical formulations of compacted granulates of β-Lactam antibiotics

ABSTRACT

The present invention discloses tablet formulations, produced by dry roller compaction comprising compacted granulates of a mixture of a medicament and an intra-granular disintegrant. The granulates are compacted together into a tablet with an extra-granular disintegrant, an optional extragranular lubricant and excipients.

This application is a continuation of Ser. No. 08/146,069 filed Jul. 14,1994 now abandoned which is a 371 of PCT/EP 92/01024 filed May 2, 1992.

The present invention relates to pharmaceutical formulations for oraladministration in the treatment of bacterial infections, and toprocesses for the manufacture of such formulations.

It is known to provide formulations for oral administration in the formof water-dispersible granules or tablets which may be swallowed ordispersed in water prior to swallowing.

In one known method of tablet manufacture, an intermediate granulate isprepared comprising an intragranular disintegrant and an active materialsuch as an antibiotic. This granulate is then mixed with anintergranular disintegrant (and optional other additives including alubricant) and compressed into tablets. Such a process, tablets andgranulate are for example described in EP 0281200A, CA 1199871 and JP3240023A.

It is desirable that such solid formulations should rapidly disperse onimmersion in water, for example by rapid disintegration of tablets.

Novel formulations have now been discovered which assist in achievingsome of the above-mentioned desirable features.

The invention therefore provides a tablet formulation having a structurecomprising compacted granulates; the granulates comprising at least onecompacted medicament optionally together with an intra-granulardisintegrant; the granulates being compacted together into a tablet formtogether with an extra-granular disintegrant and optionally alsotogether with an extra-granular lubricant, provided that if a lubricantis present the amount of lubricant is less than 0.5% by weight of thetotal tablet.

In the tablets of this invention the granulates may be in a crushedstate resulting from the compaction of the tablet, and consequently maynot have discrete boundaries, or may be sub-divided or broken up intosmaller granulates. The invention is intended to include tablets havingsuch a structure containing crushed granulates. Preferably the size ofthe granulates is in the range 100 μm to 2 mm, suitably around 1 mm±0.25mm, maximum dimension.

The medicament is preferably one which is capable of oral absorption, inparticular β-lactam antibiotics optionally in combination with aβ-lactamase inhibitor. A preferred antibiotic is amoxycillin, forexample present as a hydrate such as the trihydrate. Amoxycillin may beused alone, or may optionally be used in combination with other β-lactamantibiotics and/or β-lactamase inhibitors such as clavulanic acid orsalts (especially the potassium salt) thereof, for example in a weightratio equivalent to amoxycillin: clavulanic acid in the range 12:1 to1:1 such as around 4:1 or 2:1. Preferably the proportion of theantibiotic in the tablet is 60-98% by weight of the total tablet, in thecase of amoxycillin trihydrate calculated as the weight of thetrihydrate. Preferably the particles of antibiotic in the granulates arein the size range 1 μm to 300 μm, especially 10 μm to 200 μm. A typicalsuitable size distribution of the antibiotic particles is: >200μ 5% orless, 200-100μ 5-15%, 100-50μ 7.5-15%, <50μ 70% or more.

Suitable intra-granular disintegrants are starches, such as maize starchand rice starch, cross-linked N-vinyl-2-pyrrolidone ("CLPVP"), sodiumstarch glycollate, croscarmellose sodium and formaldehyde--casein, orcombinations thereof. A preferred intra-granular disintegrant is CLPVP,for example as marketed under the trade names Polyplasdone XL andPolyplasdone XL-10.

The granulate may consist entirely of antibiotic(s), optionally in thecase of a β-lactam antibiotic combined with a β-lactamase inhibitor, andan intra-granular disintegrant. Alternatively, particularly when thegranulate contains clavulanic acid or a salt thereof, the granulate mayalso contain a diluent such as silica gel (eg Syloid-Trade Mark).Suitable intra-granular disintegrants for use with antibiotics are CLPVPand sodium starch glycollate. Typically the proportion of intra-granulardisintegrant in the granulate may be 0.1-10 wt % of the granulate,suitably 1.0-8.0 wt %, such as 1.25-3.5 wt %. Typically the proportionof an antibiotic or antibiotic+β-lactamase inhibitor combination in thegranulate may be 99.9-90 wt %, suitably 99-92 wt %, e.g. 99-95 wt %,such as 98.75-96.5 wt % of the weight of the granulate. When thegranulate contains a diluent, this may comprise up to 30 wt % of thegranulate, but is conveniently present in a 1:1 weight ratio with theamount of clavulanic acid or its salt in the granulate. When thegranulate contains a diluent the granulate will contain acorrespondingly lower proportion of antibiotic or antibiotic+β-lactamaseinhibitor combination, for example 70-99.9 wt % of the granulate

The intimate contact between the antibiotic and the intra-granulardisintegrant in the granulate appears to assist in improveddisintegration and dispersion of the granulate in contact with water torelease antibiotic particles in the size range referred to above, and toprovide finely dispersed suspensions. Problems are associated withpreparation of granulates which include clavulanic acid or its salts,due to their hygroscopicity, and the granulate of the inventionfacilitates manufacture.

In the tablet formulation the granulate may suitably comprise 70% ormore, e.g. 80% or more, 90% or more or 95% or more of the total tabletweight so that a high proportion of medicament is present.

The extra-granular disintegrant may be a conventional disintegrant forexample starches such as maize-starch and rice starch, CLPVP, sodiumstarch glycollate, croscarmeflose sodium, microcrystalline or microfinecellulose, low-substituted hydroxypropylcellulose (i.e. cellulosepartially substituted with 2-hydroxypropyl groups, e.g. less than 25%substituted, preferably 7-16% substituted), cross-linked sodiumcarboxymethylcellulose, swellable ion exchange resins,formaldehyde-casein, or alginates. Preferred extra-granulardisintegrants are CLPVP, sodium starch glycollate, microfine celluloseand croscarmellose sodium, and combinations thereof. An example of anextra-granular disintegrant combination is a combination ofmicrocrystalline or microfine cellulose with sodium starch glycollate,croscarmellose sodium, or CLPVP, containing 80-90% by weight cellulose.

The proportion of extra-granular disintegrant to total tablet weight mayvary between broad limits, for example 0.1-25 weight %. For example ifCLPVP or sodium starch glycollate is used as extra-granular disintegrantit may suitably be used as such in a proportion 0.1-5.0 weight %,suitably 0.1-3.0 weight %, preferably 0.1-1.5 weight % of the totaltablet weight. If cellulose or a combination containing cellulose isused, e.g. as described above containing around 80-90% by weight ofcellulose, the extra-granular disintegrant may comprise 1-25 weight %,typically around 1-20 weight % of the total tablet.

Suitable lubricants are those conventional to the art, such aslong-chain fatty acids, such as stearic acid, or salts thereof, inparticular Group II metal salts, such as of magnesium or calcium.

A preferred lubricant is magnesium stearate. It is preferred to use alubricant proportion as low is possible e.g. 0.35% by weight orpreferably lower, e.g. 0.275% or less, e.g. 0.25% or less, preferablyusing no lubricant at all.

The granulate may also contain an intra-granular lubricant, which may beselected from the same materials as the extra-granular lubricant, suchas magnesium stearate. However an advantage of the present tabletformulation is that the granulate and tablet need not contain anylubricant. This can lead to improved wettability and hence improveddisintegration of the tablet. Further a reduced lubricant proportion canlead to a lower tablet weight for a given dose of antibiotic and in thecase of dispersible formulations can avoid the "smeared" appearanceassociated with higher lubricant proportions.

The tablet may also include conventional excipients, typically presentup to about 10% of the total tablet weight. These may include flavouringagents, for example flavourings such as menthol, peppermint, vanilla orfruit flavourings, flavouring agents typically being present up toaround 0.5-5% by weight of the whole tablet, and sweeteners, e.g.aspartame, present of up to around 15 mg per unit dose. Excipients mayalso include colouring agents, preservatives, suspending aids andfillers such as silicon dioxide, microcrystalline cellulose, dicalciumphosphate, lactose, sorbitol, calcium carbonate or magnesium carbonate.Such excipients are preferably mixed with the extra-granulardisintegrant and lubricant (if present). The materials present in thetablets should have low free moisture content and preferably bepre-dried. In some cases, particularly when the medicament is anantibiotic, and includes clavulanic acid or its salts, it may benecessary to include a dessiccant diluent such as silica gel as anexcipient, in a proportion of about 1-5% of the weight of theantibiotic, mixed with the antibiotic and intra-granular disintegrant inthe granulates. The particle size of the excipients does not appear tobe critical but it is desirable to exclude agglomerates.

The tablet may also contain an effervescent couple of known type, e.g. asolid acid and an alkali metal carbonate or bicarbonate which generatescarbon dioxide on contact with water to assist in disintegration of thetablet.

The tablets may be film coated in a conventional manner, e.g. forcosmetic, palatability or production purposes. Suitable coatings includehydroxypropylcellulose, acrylate andlor methacrylate co-polymers, resinsetc. Alternatively the coating may be an enteric coating, e.g. which isinsoluble in acidic gastric juice but soluble in alkaline digestivejuice. Such a coating enables the antibiotic to pass through the stomachinto the duodenum, from where it is absorbed. Suitable enteric coatingsinclude cellulose acetate phthalate.

Preferred combinations of components for the tablets of this aspect ofthe invention therefore comprise:

    ______________________________________                                                 wt %        Example                                                  ______________________________________                                        Granulate:                                                                    Component                                                                     Medicament 70-99         Amoxycillin +                                                                 Pot.clavulanate                                      Disintegrant                                                                             0.1-4         CLPVP, Microcryst.                                                            cellulose, sodium                                                             starch glycollate                                    Diluent    0-30          Silica gel                                           Tablet:                                                                       Component                                                                     Granulate  70+           above                                                Disintegrant                                                                             0.1-25        CLPVP, Microcryst.                                                            cellulose, sodium                                                             starch glycollate.                                   Lubricant  0-0.35        Magnesium stearate                                   Excipients to 100        Aspartame, flavour,                                                           colour, silicon dioxide                              ______________________________________                                    

The invention also provides a process for the manufacture of a tablet inwhich granulates comprising a compacted mixture of at least onemedicament such as a β-lactam antibiotic either alone or in combinationwith a β-lactamase inhibitor, together with an intra-granulardisintegrant are mixed with an extra-granular disintegrant andoptionally with an extra-granular lubricant and optionally with anyexcipients, provided that if a lubricant is present it amounts to lessthan 0.5% by weight of the mixture, and the mixture is compressed intotablets.

Suitable and preferred antibiotics, intra- and extra-granulardisintegrants, lubricants, excipients, granulate and particle sizes, andrelative proportions thereof are as discussed above.

The necessary granulate for the process of this aspect of the inventionmay be made in a further process by mixing the medicament in a powderedform with the intra-granular disintegrant in a dry state, and compactingthe mixture under pressure. Insofar as this further process uses asintra-granular disintegrant CLPVP, sodium starch glycollate,casein-formaldehyde, croscarmellose sodium or combinations thereof, itis believed to be novel, and is a further aspect of this invention.

In this further process, it is desirable to mill and sieve theantibiotic to achieve the desired particle size range. It is alsodesirable to mill and sieve intra-granular disintegrant to a suitableparticle size, for example in the case of CLPVP about 30μ, but particlesize does not appear to be critical.

The compaction of the mixture into granulates may be by conventional drycompaction means, for example pressing, rolling, slugging extrusion etc,and a suitable pressure for the compaction process is 30-200 KN, e.g.35-65 KN preferably 40-50 KN. The above-described granulate formulationsare particularly suited to formation by roller compaction. It may benecessary to mill and sieve the compacted mixture after compaction so asto achieve a suitable size fraction of the granulate. Compression intotablets may be carried out in a conventional manner, e.g. on aconventional tabletting machine. As an optional further step the tabletsmay be coated as described above.

When the granulates described above contain as a medicament a β-lactamantibiotic such as amoxycillin together in combination with aβ-lactamase inhibitor such as clavulanic acid or its salts (especiallypotassium clavulanate) these granulates are believed to be novel and area further aspect of this invention. Suitable and preferred features ofthese granules are as discussed above.

The granulates described above may be suitable for use in thepreparation of other pharmaceutical formulations in addition to tablets,for example they may be supplied as a free-flowing granulatedformulation in sachets containing a suitable unit dose. This may alsofor example be dissolved in water together with excipients such assweetening agents, thickeners, preservatives and buffers such as sodiumbenzoate, sodium acetate and sodium citrate to form a syrup formulation, for example for administration to small children.

The ability of the granulates to form a loose compact, and their rapiddispersion in contact with water makes them particularly suitable foruse in encapsulated formulations. Therefore in a further aspect of thisinvention there is provided an encapsulated formulation comprising suchgranulates. The encapsulated formulation may optionally include anextra-granular lubricant, which if present is suitably in an amount ofless than 0.5% by weight of the granulates, being contained within apharmaceutical capsule.

The medicament is preferably one which is capable of oral absorption, inparticular a β-lactam antibiotic optionally in combination with aβ-lactamase inhibitor. Suitable and preferred antibiotics, β-lactamaseinhibitors, intra-granular disintegrant, extra-granular lubricant,granulate and particle sizes, and relative proportions thereof for acapsule formulation are as discussed above, except that a preferredproportion of lubricant is 0.1-0.5%, particularly 0.32-0.35% by weightof the granulate.

The pharmaceutical capsule may be an entirely conventional capsule,capable of dissolving in the stomach to release its contents, forexample made of gelatine.

The formulations described above preferably contain unit doses ofantibiotic, for example 375, 500, 750 or 1000 mg of amoxycillin pertablet or capsule. The tablets may be dispersed in water prior toingestion, or may alternatively be chewed or swallowed whole.

The invention further provides a pharmaceutical formulation as describedabove, for use as an active therapeutic substance.

The invention further provides a pharmaceutical formulation as describedabove, in which the medicament is a β-lactam antibiotic optionally incombination with a β-lactamase inhibitor, for use in the treatment ofbacterial infections.

The invention further provides a method of use of a pharmaceuticalformulation as described above in which the medicament is a β-lactamantibiotic optionally in combination with a β-lactamase inhibitor in themanufacture of a medicament for use in the treatment of bacterialinfections.

The invention further provides a method of treament of bacterialinfections in mammals which comprises the administration to the mammalof an effective amount of a pharmaceutical formulation as describedabove, in whcih the medicament is a β-lactam antibiotic, optionally incombination with a β-lactamase inhibitor.

The invention will now be described by way of example only.

EXAMPLE 1 Granulate

Amoxycillin trihydrate was milled and sieved using an 0.04 or 0.027 inch(1.0-0.7 mm) aperture sieve, and was mixed for 15 minutes in a blenderwith dried cross-linked polyvinylpyrrolidone having a molecular weightof approximately 1 million and a density of 1.22 mg/cm 3 (polyplasdoneXL--Trade Mark), the mixture containing 3.4% of CLPVP by weight.

The mixture was consolidated using a roller compacter at a controlledpressure of 50 KN. The compacted flakes were granulated in a mill, orgranulated through a sieve fitted with a 1 mm mesh to obtain a suitablesize fraction.

EXAMPLE 2 Tablet

Tablets were prepared having the composition below;

    ______________________________________                                        Component    Weight mg.                                                                              Weight %                                               ______________________________________                                         Amoxycillin trihydrate                                                                     750.sup.1                                                                               78.95        as granulate of                          CLPVP        26.0      2.73         example 1                                 Sodium Starch                                                                              21.6      2.27                                                   Glycollate (Primogel)                                                         Magnesium Stearate                                                                          2.0      0.21                                                   Aspartame    20.0      2.10         extra granulate                           Microcrystalline                                                                           130.4     13.74                                                  Cellulose (Avicel                                                             PH102)                                                                        ______________________________________                                    

To prepare these tablets, the dried sodium starch glycollate, magnesiumstearate and microcrystalline cellulose were sieved, then blended withthe granulate of example 1. The aspartame was then added, and thismixture was then blended until homogeneous (5 minutes). The mixture wasthen compressed into tablets on a conventional tabletting machine.

EXAMPLE 3 Granulate

A granulate was prepared using a procedure identical to example 1,comprising 97 weight % of amoxycillin trihydrate and 3 weight %polyplasdone XL, and using a controlled pressure of 40-50 KN.

EXAMPLE 4 Tablet

Tablets were prepared having the composition below:

    ______________________________________                                        Component                                                                              wt. mg   wt. mg   wt. mg wt. mg wt. %                                ______________________________________                                        Amoxycillin                                                                            375      500      750    1000   83.00.sup.1                          CLPVP    17.5     23.33    35     46.65  3.78.sup.2                           Peppermint                                                                             3        4        6      7.99   0.65                                 dry flavour                                                                   Aspartame                                                                              7.5      10       15     19.99  1.62                                 Magnesium                                                                              1        1.34     2      2.67   0.21                                 stearate                                                                      ______________________________________                                         .sup.1 As 95 wt. % of amoxycillin trihydrate.                                 .sup.2 3% as intragranular, and 0.78% as extragranular disintegrant.     

To prepare these tablets, the dried flavour, aspartame, magnesiumstearate and a weight of CLPVP (polyplasdone XL) corresponding to 0.78wt. % of the total weight of the mixture was mixed for 5 minutes withthe granulate of example 3 to give the wt % indicated above. The mixturewas then compressed into tablets on a conventional tabletting machine.

Typical tablets of this example containing 750 mg of amoxycillin as thetrihydrate had the following characteristics:

weight: 925 mg±5%

hardness: >16 KP

time of dispersal: <1 minute

in water

friability: <1%

presentation: Oval, 17×10×7 mm tablets

EXAMPLE 5 Granulate

A granulate was prepared using a procedure identical to that of example1, comprising 97.12 weight % amoxycillin trihydrate together with 2.88weight % sodium starch glycollate (as "Primogel") as intra-granulardisintegrant.

EXAMPLE 6 Tablet

Tablets were prepared having the composition below:

    ______________________________________                                        Component    Weight mg.                                                                              Weight %                                               ______________________________________                                         Amoxycillin                                                                               750     mg.sup.1                                                                             78.95                                             Sodium starch                                                                             21.6    mg      2.27      as granulate                            glycollate                            of example 5                             Magnesium stearate                                                                        20      mg      0.21                                             Dried microcrystalline                                                                    to 950  mg     18.57      extra granulate                         cellulose (Avicel                                                             PH102)                                                                        ______________________________________                                         .sup.1 As free acid equivalent                                           

To prepare these tablets, the granulate of example 5 was sieved using a1 mm sieve, and was then blended with appropriate quantities of themagnesium stearate (lubricant) and microcrystalline cellulose, mixingfor 15 minutes. The mixture was then compacted to form tablets havingthe following characteristics:

weight: 950 mg

hardness: 12-16 KP

time of dispersal: 10-15 seconds (37° C.),

in water 20-25 seconds (20° C.)

These tablets could be provided in the above-described uncoated statefor dispersion in water prior to swallowing, or could be film coated forswollowing.

EXAMPLE 7 Encapsulated Formulation

The granulate of example 3 was made up into a loose compact under gentlepressure together with an amount of magnesium stearate lubricant tototal 0.34% by weight of the total compact. This loose compact wassealed into gelatin capsules containing the following mixture:

    ______________________________________                                        Component        Weight mg.                                                                              Weight %                                           ______________________________________                                        Amoxycillin trihydrate                                                                         573.91.sup.1                                                                            96.8                                               CLPVP            17        2.9                                                magnesium stearate                                                                             2         0.34                                               ______________________________________                                         .sup.1 corresponds to 500 mg amoxycillin free acid                       

EXAMPLE 8 Sachet Formulation

    ______________________________________                                        Component    Weight mg.                                                                              Weight %                                               ______________________________________                                        Amoxycillin trihydrate                                                        Potassium    2711.1    76.12                                                  clavulanate/syloid AL-1             granulate                                 blend 1:1                                                                     Polyasdone XL dried                                                           Polyplasdone XL dried                                                                      13.5      0.38                                                   Lemon dry flavour                                                                          408.0     11.45                                                  Strawberry dry flavour                                                                     132.0     3.71                                                   Peach dry flavour                                                                          102.0     2.86         extra granular                            Aspartame    45.0      1.26                                                   Xantham Gum  150.0     4.21                                                   ______________________________________                                    

Granules were in a manner identical to that of example 1, i.e. bymilling and sieving of the granulate components, followed by rollercompaction (50 KN) and granulation. The granules could be made up into amixture suitable for a sachet presentation with the extra-granularexcipients.

The granulate of this example could be supplied contining appropriateweights of amoxycillin/clavulanate in a sachet, and is also suitable formaking up into syrup formulations. For example the weights listed may bemade up into 60 ml to produce a 156.25 mg/5 ml syrup or double thelisted weights may be made up into 60 ml to produce a 312.5 mg.5 mlsyrup. These syrups do not contain any added sugar.

EXAMPLE 9 Granulate

    ______________________________________                                        Component    Weight mg.                                                                              Weight %                                               ______________________________________                                        Amoxycillin trihydrate                                                                     581.4.sup.1                                                                             64.0                                                   Potassium clavulanate                                                                      152.4.sup.2                                                                             16.8                                                   Syloid AL-1  152.4     16.8         as granulate                              Polyplasdone XL dried                                                                      22.0      2.42                                                   ______________________________________                                         .sup.1 corresponds to 500 mg amoxycillin free acid.                           .sup.2 corresponds to 125 mg free clavulanic acid.                       

Granules are prepared using this mixture in a manner identical to thatof example 8. These granules are suitable for supply in a sachet,together with flavour and sucrose in the proportions listed below forthe quantity of granules listed above per sachet:

    ______________________________________                                        Lemon dry flavour                                                                              136.0        mg                                              Strawberry dry flavour                                                                         44.0         mg                                              Peach dry flavour                                                                              34.0         mg                                              Sucrose          to 3500      mg                                              ______________________________________                                    

Sachets containing other weights of amoxycillin, e.g. 250 or 125 mgcould be made up using proportional amounts of the weights listed andmade up to 1750 mg total weight with sucrose.

EXAMPLE 10 Tablet

    ______________________________________                                        Component    Weight mg.                                                                              Weight %                                               ______________________________________                                        Amoxycillin trihydrate                                                                     581.4.sup.1                                                                             61.2                                                   Potassium clavulanate                                                                      152.4.sup.2                                                                             16.0                                                   Syloid AL-1  152.4     16.0         as granulate                              Polyplasdone XL dried                                                                      17.4      1.83                                                   Dry flavour (Peppermint                                                                    6.0       0.63                                                   or mandarin)                                                                  Polyplasdone XL dried                                                                      25.0      2.63                                                   Aspartame    15.0      1.58         extra granulate                           Colouring    5.0       0.53                                                   Magnesium stearate                                                                         2.5       0.26                                                   ______________________________________                                         .sup.1 corresponds to 500 mg amoxycillin free acid.                           .sup.2 corresponds to 125 mg free clavulanic acid.                       

Granules are prepared using this mixture in a manner identical to thatof example 8. The flavour, polyplasdone XL, colouring and magnesiumstearate were sieved then blended with the granulate. The aspartame wasthen added, and this mixture was then compressed into tablets on aconventional tabletting machine. This tablet contains 625.0 mg of theamoxycillin: clavulanate combination, and the quantities used may behalved to prepare a tablet containing 312.5 mg.

EXAMPLE 11 Tablet

    ______________________________________                                        Component    Weight mg.                                                                              Weight %                                               ______________________________________                                        Amoxycillin trihydrate                                                                     290.7.sup.1                                                                             46.3                                                   Potassium clavulanate                                                                      152.4.sup.2                                                                             24.3                                                   Syloid AL-1  152.4     24.3         as granulate                              Polyplasdone XL dried                                                                      8.7       1.38                                                   Dry flavour (Peppermint                                                                    3.0       0.48                                                   or mandarin)                                                                  Polyplasdone XL dried                                                                      12.5      2.00                                                   Aspartame    7.5       1.19         extra granulate                           Colouring    2.5       0.39                                                   Magnesium stearate                                                                         1.25      0.20                                                   ______________________________________                                         .sup.1 corresponds to 250 mg amoxycillin free acid.                           .sup.2 corresponds to 125 mg free clavulanic acid.                       

Tablets were made from this mixture using a procedure identical to thatof example 10.

EXAMPLE 12 Sachet or Syrup Formulations

    ______________________________________                                        Component              Weight mg w + %                                        ______________________________________                                        Amoxycillin: potassium         2255.6  63.3                                   clavulanate                                                                                         granulate.sup.1                                         4:1 w:w + 3 wt % CLPVP                                                        CLPVP                          13.5    0.38                                   Lemon dry flavour              408.0   11.46                                  Strawberry dry flavour         132.0   3.71                                   Peach dry flavour              102.0   2.86                                   Silicon dioxide USNF (Syloid   450.0   12.64                                  AL-1)                                                                         Aspartame                      45.0    1.26                                   Xantham gum                    150.0   4.21                                   Total weight                   3561.6  100.0                                  ______________________________________                                         .sup.1 amox: clav expressed as free acid.                                

The granulate was prepared using the procedure of example 8. Thisformulation could be supplied in a sachet, or could be made up into asyrup, for example at concentrations of 3561.6 mg/60 ml or 7123.2 mg/60ml or 7123.2 mg/60 ml (=156.25 and 312.5 mg amoxycillin: clavulanate/5ml respectively). To adjust the syrup to a suitable viscosity and pH,aerosil 200, succinic acid and/or methocel E-15 (dry) may be used.

EXAMPLE 13 Sachet Formulation

    ______________________________________                                        Component    Weight (mg)         w + %                                        ______________________________________                                        Granulate                                                                     (Amox:Kclav                                                                   4:1 or 7:1 +     500     250   125   875    7-25                              3% PVP)                                                                       Lemon dry flavour                                                                              136     68    34    .sup. 136)                               Strawberry dry    44     22    11    .sup.   3-6.1                            flavour                                                                       Peach dry flavour                                                                               34     17    8.5   .sup.  34)                               Silicon Dioxide  150     75    37.5  150   2.1-4.3                            U.S.N.F.                                                                      (Syloid AL-1)                                                                 Sucrose to       3500    1750  1750  3500  to 100                             ______________________________________                                         .sup.1 weights and Amox/Kclav expressed as free acid.                    

The granulate was prepared using the procedure of example 8, and wasthen mixed with the other excipients.

EXAMPLE 14 Tablet Formulation

    ______________________________________                                        Component  weight (mg)          w + %                                         ______________________________________                                        Amox: clav.sup.1                                                                         4:1    4:1      2:1   7:1                                          Granulate 2                                                                              751.9  376.0    452.1 1201.3 70.90                                 Dry Flavour 3                                                                            6.0    3.0      3.0   8.0    0.48-0.63                             Poliplasdone XL)                                                                         100.0  50.0     66.5  110.0   8.1-10.7                             dried)                                                                        Aspartame  15.0   7.5      7.5   15.0   1.1-1.6                               Colouring  4-5    2-2.5    2-2.5 4-5    0.3-0.55                              Mag. Stearate                                                                            2.5    1.25     1.25  3.4    0.19-0.26                             Silicon Dioxide)                                                              Syloid AL-1) to                                                                          950    475      628   1350   to 100                                ______________________________________                                         .sup.1 Amox: clav expressed as weight: weight of amoxycillin: clavulanate     free acid.                                                                    2 Granulate = amox: clav + 3% CLPVP.                                          3 Peppermint or mandarin.                                                

The granulate was prepared using the procedure of example 9.

The granulate was prepared using the procedure of example 9. The otherexcipients except aspartame were sieved and blended then mixed with thegranulate. The aspartame was then added, and this mixture was thencompressed into tablets in a conventional tabletting machine. Thistablet contained 625 mg of the amoxycillin: clavulante blend. Tablets ofdifferent strengths could be formulated correspondingly, eg containing1000, 375 or 312.5 mg of the amoxycillin: clavulanate combination.

EXAMPLE 15 Tablet Formulation

    ______________________________________                                        Component     Weight (mg)       w + %                                         ______________________________________                                        Granulate         751.9   376.0                                                                              188.0                                                                              1201.3                                                                              71-83                               (Amox.Kclav)                                                                  4:1 or 7:1 + 3% PVP                                                            Magnesium stearate                                                                              2.6     1.3  0.65                                                                               3.9   0.25-0.27                          Ph. Eur                                                                       Silicon Dioxide   44.0    22.0 11.0 44.0    3-4.25                            USP/NE (Syloid                                                                AL-1)                                                                         Microcrystalline cellu-                                                                         850.0   425.0                                                                              212.5                                                                              1275.0                                                                              1.8-5                               lose Avicel pH 112                                                            dried . . . to . . .                                                          Organic film coating                                                                            yes     yes  yes  yes   to 100                              Actual weight     1050.0  --   --   1450.0                                    ______________________________________                                         .sup.1 amox: clav expressed as free acid.                                

The tablet was made up in a manner identical to that of example 14.

The weights and relative proportions of the components of examples 1 to15 could be varied about the figures listed, but suitably are within±10% of those listed, desirably within ±5%, especially ±2.5%.

We claim:
 1. A process for the manufacture of a pharmaceutical tablet,in which granulates comprising a medicament which comprises amoxycillinoptionally in combination with a salt of clavulanic acid in a weightratio equivalent to amoxycillin: clavulanic acid in the range 12:1 to1:1, optionally together with an intra-granular disintegrant; whichgranulates are prepared by dry roller compaction, are mixed with anextra-granular disintegrant and optionally with an extra-granularlubricant and excipients, provided that if a lubricant is present itamounts to less than 0.5% by weight of the mixture, and the mixture iscompressed into tablets.
 2. A process for the manufacture of apharmaceutical granulate, in which a medicament which is amoxycillintogether in combination with a β-lactamase inhibitor is dry rollercompacted, and with an intra-granular disintegrant.
 3. The processaccording to claim 1 wherein clavulanic acid or a salt thereof isincluded in the granulate.
 4. The process according to claim 1 whereinthe granulate includes an intra-granular disintegrant selected from thegroup consisting of maize starch, rice starch, microcrystallinecellulose, CLPVP, sodium starch glycollate, croscarmellose sodium,formaldehyde-casein or combinations thereof.
 5. The process according toclaim 1 wherein the granulate has a proportion of intra-granulardisintegrant from 0.1 to 10 wt % of the granulate.
 6. The processaccording to claim 1 wherein the granulate comprises a medicament whichis amoxycillin or amoxycillin+clavulanic acid or a salt thereof incombination, an intra-granular disintegrant which is CLPVP or sodiumstarch glycollate, and optionally one or more diluent(s), in aproportion 70-99% medicament, 1-5 wt % disintegrant and up to 30 wt %diluent.
 7. The process according to claim 1 wherein the granulatecomprises 70% or more of the tablet weight.
 8. The process according toclaim 1 wherein the extra-granular disintegrant is selected from thegroup consisting of maize starch, rice starch, CLPVP, sodium starchglycollate, croscarmellose sodium, microcrystalline or microfinecellulose, low-substituted hydroxypropylcellulose, cross-linked sodiumcarboxymethylcellulose, swellable ion exchange resins,formaldehyde-casein or alginates.
 9. The process according to claim 1wherein the proportion of extra-granular disintegrant in the tablet isbetween 0.1-25% wt % of the total tablet weight.
 10. The processaccording to claim 2 wherein the β-lactamase inhibitor is clavulanicacid or a salt thereof.
 11. The process according to claim 2 wherein thegranulate includes an intra-granular disintegrant selected from thegroup consisting of maize starch, rice starch, microcrystallinecellulose, CLPVP, sodium starch glycollate, croscarmellose sodium,formaldehyde-casein or combinations thereof.
 12. The process accordingto claim 2 wherein the granulate has a proportion of intra-granulardisintegrant from 0.1 to 10 wt % of the granulate medicament which isamoxycillin+clavulanic acid or a salt thereof in combination, anintra-granular disintegrant which is CLPVP or sodium starch glycollate,and optionally one or more diluent(s), in a proportion 70-99%medicament, 1-5 wt% disintegrant and up to 30 wt % diluent.
 13. Theprocess according to claim 2 wherein the granulate optionally contains alubricant.
 14. The process according to claim 2 wherein the medicamentis amoxycillin and clavulanic acid or a salt thereof, and the granulatecontains an intra-granular disintegrant which is CLPVP or sodium starchglycollate, and optionally one or more diluent(s), in a proportion70-99% medicament, 1-5 wt % disintegrant and up to 30 wt % diluent. 15.A process for the manufacture of a pharmaceutical granulate, in which amedicament which is amoxycillin is dry roller compacted together with anintra-granular disintegrant.
 16. The process according to claim 15wherein the granulate includes an intra-granular disintegrant selectedfrom the group consisting of maize starch, rice starch, microcrystallinecellulose, CLPVP, sodium starch glycollate, croscarmellose sodium,formaldehyde-casein or combinations thereof.
 17. The process accordingto claim 15 wherein the granulate has a proportion of intra-granulardisintegrant from 0.1 to 10 wt % of the granulate.
 18. The processaccording to claim 15 wherein the granulate optionally contains alubricant.
 19. The process according to claim 15 wherein the granulatecontains an intra-granular disintegrant which is CLPVP or sodium starchglycollate, and optionally one or more diluent(s), in a proportion70-99% medicament, 1-5 wt % disintegrant and up to 30 wt % diluent. 20.The process according to claim 2 wherein the weight ratio ofamoxycillin: β-lactamase inhibitor is in the range of 7:1.
 21. Theprocess according to claim 2 wherein the weight of amoxycillin:β-lactamase inhibitor is in the range of 2:1.
 22. The process accordingto claim 1 wherein the weight ratio of amoxycillin:clavulanic acid is inthe range of 7:1.
 23. The process according to claim 1 wherein the ratioof amoxycillin:clavulanic acid is in the range of 2:1.
 24. The processaccording to claim 4 wherein the intragranulate disintegrantisN-vinyl-2-pyrrolidone (CLPVP).
 25. The process according to claim 11wherein the intragranulate disintegrant isN-vinyl-2-pyrrolidone (CLPVP).26. The process according to claim 16 wherein the intragranulatedisintegrant isN-vinyl-2-pyrrolidone (CLPVP).